It is known that skin responds to androgens and is an active site of androgen metabolism. The androgen testosterone is metabolized in the skin to dihydrotestosterone (DHT) which is a more potent androgen than testosterone. As set out in Arch., Dermatol. 111, 1496 (1975) there is considerable evidence that DHT is involved in the pathogenesis of acne as well as other androgen associated conditions. Studies in the hamster flank organ, which is an androgen dependent sebaceous structure, indicate that DHT stimulates the growth of this structure. It has been found that acne-bearing skin produces from 2 to 20 times more DHT than normal skin. Therefore, it is believed that agents capable of blocking the formation of DHT would be effective in the treatment of an acne condition. Also, many studies indicate that prostatic hypertrophy may be treated by administering an agent that prevents the formation of DHT from testosterone, that is, a testosterone 5.alpha.-reductase inhibitor. Testosterone is converted to DHT by the enzymatic action of testosterone 5.alpha.-reductase. One possible means of blocking the formation of DHT is to inhibit the activity of testosterone 5.alpha.-reductase. More desirably, in the treatment of acne the activity of the 5.alpha.-reductase enzymes is inhibited locally, that is in the region of the acne-bearing skin.
Many workers in the art have believed that steroid compounds effective for testosterone 5.alpha.-reductase inhibition purposes required a .DELTA..sup.4 -3-keto configuration and inferentially, at least presence of other ring A substituents would add little, and might even detract from the usefulness of a compound for inhibition purposes.
Thus, the numerous compounds discussed by Voigt and Hsia in their U.S. Pat. No. 3,917,829 and by Benson and Blohm in their U.S. Pat. No. 4,088,760 all contain the ring A .DELTA..sup.4 -3-one structure.
It may be noted that the .DELTA..sup.4 -3 keto steroids heretofore suggested for inhibition of the 5.alpha.-reductase act through competitive inhibition and their effectiveness depends upon maintaining a significant, perhaps substantial, concentration of inhibitor in the target organ, e.g., in the patient's skin or in the prostate. Manifestly competitive inhibitors offer a lesser degree of effectiveness than an irreversible or quasi-irreversible inhibitors.
A theory for irreversible inhibition of a 5.alpha.-reductase and .DELTA..sup.5 -3-keto isomerase has been offered in U.S. Pat. No. 4,087,461, to which reference is made for details of the theory. Briefly the theory calls for employment of a steroid containing a potentially reactive group, which group becomes reactive when the target enzyme carries out its transformation. At that time a chemical reaction ensues, e.g., an alkylation, directly at the active site of the enzyme or so closely adjacent thereto as to irreversibly inhibit the enzyme. U.S. Pat. No. 4,087,461 suggests allenic seco-steroids for irreversible inhibition of .DELTA..sup.5 -3-keto steroid isomerases and of testosterone 5.alpha.-reductase. U.S. Pat. No. 4,087,461 describes the enzyme catalyzed transformation as involving reaction at the C-4 position.
The present invention relates to use of certain 4-substituted steroids which inhibit the activity of 5.alpha.-reductase rendering said compounds useful in treating acne or oily skin. It is not known whether the inhibition is irreversible or is near to irreversible, i.e., quasi-irreversible, because the 4-substituted steroid does not readily decouple from the enzyme.